This application is in response to the [unreadable]Metals in Medicine[unreadable] program (PA-08-251). Iron deficiency is the most common human nutritional deficiency disease. Recent estimates of the prevalence of iron deficiency ranges from 2% to 22% of Americans depending on age and gender. Since iron deficiency impairs work output due to muscle dysfunction as well as cognitive development and increases the incidence of low birthweight and preterm delivery there is much interest in understanding its etiology and reducing its prevalence. Much is understood concerning how the uptake and metabolic fate of iron is controlled in relation to iron status. However, relatively little is known concerning the adaptive changes in other metabolic pathways that occur to enhance cell viability when iron supply is not adequate. In animals, iron metabolism is largely controlled by two RNA binding proteins, iron regulatory protein 1 (IRP1) and IRP2. IRPs regulate the synthesis of ferritin (iron storage), transferrin receptor 1 (iron uptake) and other proteins of iron metabolism. It has recently become clear that IRPs also control the fate of mRNAs whose function is critical for the adaptive response to iron deficiency. We have demonstrated that synthesis of the tricarboxylic acid cycle enzyme mitochondrial aconitase (m-acon) is regulated by IRPs. On the basis of our findings we propose that IRP-dependent repression of m-acon in dietary iron deficiency enhances the export of citrate from mitochondria. We propose that the enhancement of citrate export by IRPs in iron deficiency allows increased generation of isocitrate by cytosolic aconitase. The isocitrate so-formed is used to combat oxidative stress and enhance oxygen regulation of gene expression, both of which are key adaptive processes need to enhance cell function and survival in iron deficiency. Consequently, the specific aims of this proposal are to determine the role of: 1) m-acon abundance and activity in controlling mitochondrial export of citrate;2) cytosolic citrate in the adaptive response (of liver) to iron deficiency. Our studies will identify novel links between the fields of iron metabolism, oxidative stress and oxygen signaling by demonstrating that IRPs are critical components of a novel retrograde pathway that links mitochondrial function to the adaptive response to iron deficiency.